The emergence of letermovir and maribavir drug-resistant mutations: from clinical trials to real-world studies.

PURPOSE OF REVIEW: Cytomegalovirus (CMV) infection is associated with severe clinical disease and high morbidity in immunocompromised hosts. Letermovir and maribavir, are two recently developed antiviral drugs used in the prevention and treatment of resistant and refractory CMV. Following the publication of landmark randomized trials and increased use, both clinical trial data and real-world experience has reported the development of antiviral drug resistance. The aim of this review was to comprehensively review the published literature on letermovir and maribavir drug resistance and to describe the clinical scenarios in which they may emerge. RECENT FINDINGS: For letermovir, the most frequently detected resistance mutations occur in the UL56 gene (C325Y/W/F) and confer total resistance. Maribavir resistance mutations most often occur in the UL97 gene and resistance-associated variants (RAVs) T409M, H411Y, C480F have all been detected. The clinical context in which letermovir and maribavir resistance occurs include high viral loads at initiation, intensified immunosuppression, subtherapeutic drug exposure because of poor adherence, drug interactions, and inadequate central nervous system (CNS) penetration. Emergence of resistance mutations generally occurs within the first 3 months of initiation. SUMMARY: The detection of letermovir and maribavir resistance mutations highlights an ongoing clinical challenge in the management of CMV.

Non-viral pathogens of infectious diarrhoea post-allogeneic stem cell transplantation are associated with graft-versus-host disease.

Infectious diarrhoea is common post-allogeneic haematopoietic stem-cell transplantation (alloHSCT). While the epidemiology of Clostridioides difficile infection (CDI) post-alloHSCT has been described, the impact of other diarrhoeal pathogens is uncertain. We reviewed all alloHSCT between 2017 and 2022 at a single large transplant centre; 374 patients were identified and included. The 1-year incidence of infectious diarrhoea was 23%, divided into viral (13/374, 3%), CDI (65/374, 17%) and other bacterial infections (16/374, 4%). There was a significant association between infectious diarrhoea within 1 year post-transplant and the occurrence of severe acute lower gastrointestinal graft-versus-host disease (GVHD, OR = 4.64, 95% CI 2.57-8.38, p < 0.001) and inferior GVHD-free, relapse-free survival on analysis adjusted for age, donor type, stem cell source and T-cell depletion (aHR = 1.64, 95% CI = 1.18-2.27, p = 0.003). When the classes of infectious diarrhoea were compared to no infection, bacterial (OR = 6.38, 95% CI 1.90-21.40, p = 0.003), CDI (OR = 3.80, 95% CI 1.91-7.53, p < 0.001) and multiple infections (OR = 11.16, 95% CI 2.84-43.92, p < 0.001) were all independently associated with a higher risk of severe GI GVHD. Conversely, viral infections were not (OR = 2.98, 95% CI 0.57-15.43, p = 0.20). Non-viral infectious diarrhoea is significantly associated with the development of GVHD. Research to examine whether the prevention of infectious diarrhoea via infection control measures or modulation of the microbiome reduces the incidence of GVHD is needed.

Evidence supporting the use of therapeutic drug monitoring of ganciclovir in transplantation.

PURPOSE OF REVIEW: This review describes current knowledge of ganciclovir (GCV) and valganciclovir (ValGCV) pharmacokinetic/pharmacodynamic characteristics, highlighting the likely contribution from host genetic factors to interpatient variability. The evidence and challenges surrounding optimization of drug dosing through therapeutic drug monitoring (TDM) are examined, with recommendations made. RECENT FINDINGS: Pharmacokinetic studies of current dosing guidelines have shown high interindividual and intraindividual variability of GCV concentrations. This is sometimes associated with a slow decline in cytomegalovirus (CMV) viral load in some transplant recipients. A high incidence of GCV-associated myelosuppression has limited the use of this drug in the transplant setting. Patient groups identified to benefit from GCV TDM include pediatric patients, cystic fibrosis with lung transplantation, obese with kidney transplantation, and patients with fluctuating renal function or on hemodialysis. The emergence of refractory resistant CMV, particularly in immune compromised patients, highlights the importance of appropriate dosing of these antivirals. Host genetic factors need to be considered where recently, two host genes were shown to account for interpatient variation during ganciclovir therapy. Therapeutic Drug Monitoring has been shown to improve target antiviral-level attainment. The use of TDM may guide concentration-based dose adjustment, potentially improving virological and clinical outcomes. However, evidence supporting the use of TDM in clinical practice remains limited and further study is needed in the transplant cohort. SUMMARY: Further studies examining novel biomarkers are needed to guide target concentrations in prophylaxis and treatment. The use of TDM in transplant recipients is likely to improve the clinical efficacy of current antivirals and optimize outcomes in transplant recipients.

CMV prevention strategies in allogeneic hematopoietic cell transplantation; the role of prophylaxis and pre-emptive monitoring in the era of letermovir.

The preferred strategy for preventing CMV in at-risk populations in alloHCT has undergone a significant practice shift in recent years where the pendulum has swung from a pre-emptive approach to now offering letermovir prophylaxis to all CMV seropositive recipients. Letermovir prophylaxis has resulted in significant reductions in post-transplant clinically significant CMV infection (csCMVi) as well as other important outcomes such as CMV disease, resistant, and refractory CMV infections and nonrelapse mortality. However, prophylactic strategies are not without some limitations, namely delayed onset CMV infections, delayed CMV-specific T cell immune reconstitution, increased drug costs and limited data within pediatric populations. Thus, this review aims to provide an overview of prophylaxis and pre-emptive CMV preventative strategies, and how they are applicable in the current era of letermovir prophylaxis.

Effective CMV prophylaxis with high-dose valaciclovir in allogeneic hematopoietic stem-cell recipients at a high risk of CMV infection.

BACKGROUND: Cytomegalovirus (CMV) infection increases mortality and morbidity following allogeneic hematopoietic stem-cell transplantation (alloHSCT). Universal antiviral prophylaxis with letermovir is effective but unsubsidized in Australia. Valaciclovir demonstrates anti-CMV activity in high doses, but few current real-world studies explore its use as primary prophylaxis in high-risk patients post-alloHSCT. METHODS: We performed a retrospective analysis of alloHSCT recipients at high risk of clinically significant CMV infection (cs-CMVi), defined as a plasma CMV DNA viral load of >400 IU/ml requiring preemptive therapy, or CMV disease. High-risk recipients were CMV seropositive and underwent T-cell depleted, haploidentical or umbilical cord stem-cell transplants. Consecutive patients transplanted from July 2018 to January 2020, treated with valaciclovir 2 g TDS from day +7 to +100 (HD-VALA), were compared to a historical cohort (July 2017-June 2018) who only received preemptive CMV therapy, and standard valaciclovir (SD-VALA) for varicella/herpes prophylaxis. We compared incidence of and time to cs-CMVi. RESULTS: In the SD-VALA cohort (n = 27, median CMV follow-up duration 259 days), 23/27 (85%) developed cs-CMVi at a median of 39 days. For the HD-VALA cohort (n = 35, median CMV follow-up duration 216 days), 19/35 (54%) developed cs-CMVi, at a median of 68 days. Time to cs-CMVi was significantly longer in HD-VALA cohort (p < .0001). On multivariate analysis, HD VALA reduced the risk of cs-CMVi (HR 0.32, p = .0005). CONCLUSIONS: In alloHSCT recipients at high risk for cs-CMVi, HD-VALA resulted in lower cumulative reactivation, and delayed reactivation, reducing requirement for preemptive CMV therapy in the early post-engraftment period.

Risk factors and outcome of concurrent and sequential multiviral cytomegalovirus, Epstein-Barr virus, BK virus, adenovirus and other viral reactivations in transplantation.

PURPOSE OF REVIEW: Reactivation of viral infections occurs frequently in immunosuppressed populations, particularly in solid organ (SOT) or allogeneic haematopoietic cell (HCT) transplant patients. Concurrent and sequential multivirus infections are common, yet risk factors and outcomes remain unclear. This review aims to identify the patients vulnerable to multivirus infections and characterize the impact of increased viral burden to formulate prevention and treatment strategies. RECENT FINDINGS: Incidences of up to 89% in SOT and 36% in HCT have been reported for two viruses, and 32% in SOT and 28% in HCT for at least three viruses. Risk factors appear related to an increased burden of immunosuppression, with most viral coinfections occurring within 12 months of transplantation. Direct viral complications such as cytomegalovirus disease are more frequent in coinfected patients, with documented prolonged duration of viraemia, higher viral load and increased end-organ disease. Graft dysfunction, acute rejection and graft-vs.-host disease (GVHD) have also been associated. Increased mortality is reported in the HCT population. SUMMARY: Multivirus infections occur in a significant proportion of transplant patients and is linked to immunosuppressive burden. There is increasing evidence that this leads to worse graft and patient outcomes. Further prospective studies are required to further comprehensively characterise viral epidemiology, mechanisms and treatment strategies to ameliorate this risk.

Cytomegalovirus DNAemia and disease: current-era epidemiology, clinical characteristics and outcomes in cancer patients other than allogeneic haemopoietic transplantation.

BACKGROUND: High-intensity chemotherapy and advances in novel immunotherapies have seen the emergence of cytomegalovirus (CMV) infections in cancer patients other than allogeneic haemopoietic cell transplantation (HCT). Aim To evaluate the epidemiology, clinical characteristics and outcomes of CMV infection in this population. METHODS: A retrospective review of cancer patients other than allogeneic HCT who had CMV DNAemia and/or disease from July 2013 till May 2020 at a quaternary cancer centre was performed. RESULTS: Of 11 485 cancer patients who underwent treatment during this period, 953 patients had CMV DNA testing performed and 238 of them had CMV DNAemia. After excluding patients with allogeneic HCT, 62 patients with CMV DNAemia were identified, of whom 10 had concurrent CMV disease. The most frequent underlying malignancies were B-cell lymphoproliferative disease (LPD) (31%; 19/62), T-cell LPD (21%; 13/62), chronic lymphocytic leukaemia (11%; 7/62) and multiple myeloma (10%; 6/62). Most patients had lymphopenia (77%; 48/62), multiple cancer therapies (63%; 39/62 received ≥2 previous therapies), co-infection (56%; 35/62 had ≥1 co-infection) and corticosteroid therapy (48%; 30/62) within 1 month before CMV diagnosis. CMV DNAemia and disease were observed in patients receiving novel immunotherapies, including bispecific antibody therapy, chimeric-antigen receptor T-cell therapy and immune checkpoint inhibitors. CONCLUSION: Patients with haematological malignancy, particularly B-cell LPD, T-cell LPD, chronic lymphocytic leukaemia and multiple myeloma, were frequently identified to have CMV DNAemia and disease. Lymphopenia, multiple cancer therapies, co-infection and recent receipt of systemic corticosteroids were also commonly observed. Future studies are necessary to determine optimal identification and management of CMV in these patients.

Beyond antivirals: virus-specific T-cell immunotherapy for BK virus haemorrhagic cystitis and JC virus progressive multifocal leukoencephalopathy.

PURPOSE OF REVIEW: The clinical manifestations of the polyomaviruses BK and JC in immunocompromised patients include BK virus (BKV) induced haemorrhagic cystitis and nephropathy, and JC virus (JCV) associated progressive multifocal leukoencephalopathy (PML) and are typically a consequence of impaired adaptive immunity in the host. To date, little clinical success has been achieved with antiviral agents or other drug therapies to treat these conditions. Here we review the methods and outcomes of the most recent clinical studies utilising adoptive immunotherapy with BK and/or JC virus-specific T-cells (VST) as either prophylaxis or treatment alternatives. RECENT FINDINGS: In the last 12-18 months, several clinical trials have been published in the post-haemopoietic stem cell transplant (HSCT) setting showing good clinical success with the use of VST for treatment of BK viremia ± haemorrhagic cystitis. Between 82 and 100% clinical response has been observed in haemorrhagic cystitis using either third-party or donor-derived VST. The therapy was well tolerated with few cases of graft versus host disease in HSCT recipients, but immune mediated renal allograft loss was observed in one renal transplant recipient. Studies using BKV/JCV VST to treat PML are hindered by few patients who are sufficiently stable to receive VST. In a condition that otherwise carries such poor prognosis, VST were associated with clearance of JC virus, clinical and radiological improvement in some patients. Immune reconstitution inflammatory syndrome was a noted adverse event. SUMMARY: Restoration of BK and JC virus immunity using VST immunotherapy has shown good clinical outcomes in BKV associated infections. Further evaluation with the administration of VST earlier in the course of disease is warranted for the treatment of BKV associated nephropathy in renal allograft and in JCV PML. In both indications, larger cohorts and standardisation of dosing and outcome measures would be of benefit.

Cytomegalovirus in primary immunodeficiency.

PURPOSE OF REVIEW: Cytomegalovirus (CMV) infection and disease are well described in the setting of secondary immunodeficiency. Less is known about CMV in the context of primary immunodeficiencies (PIDs), where inborn errors in one or more arms of the immune system result in variable degrees of CMV susceptibility. RECENT FINDINGS: PID presents unique challenges in the diagnosis and management of CMV disease. The clinical presentation of CMV in PID is often severe, accelerated by underlying immune dysregulation and iatrogenic immunosuppression. Here we describe the clinical significance of CMV infection in PID, the key components of immune defence against CMV and how these are affected in specific PIDs. CMV disease is under-recognized as a complication of common variable immunodeficiency (CVID). High rates of CMV end-organ disease, mortality, development of CMV resistance and prolonged antiviral use have been observed in individuals with CVID. SUMMARY: We recommend that clinicians tailor their approach to the individual based on their underlying immune deficit and maintain a high index of suspicion and low threshold for treatment. More research is required to improve stratification of CMV risk in PID, develop new diagnostic tools and manage end-organ disease in this cohort.

Safety and efficacy of intravenously administered cidofovir in adult haematopoietic cell transplant recipients: a retrospective multicentre cohort study.

OBJECTIVES: To evaluate the safety and efficacy of cidofovir for the treatment of double-stranded DNA (dsDNA) viral infections following allogeneic haematopoietic cell transplant (HCT). METHODS: This was a retrospective multicentre cohort study including adult HCT recipients who received ≥1 dose of IV-administered cidofovir for any dsDNA viral infection from 2006 to 2019. The objectives were to describe the rate of and risk factors for nephrotoxicity and virological response by the end of treatment (EOT). RESULTS: We included 165 patients from nine centres. Cidofovir was administered at 5 mg/kg/week (N = 115; 69.7%), 1 mg/kg/week (18; 10.9%), 3 mg/kg/week (12; 7.3%) or 1 mg/kg three times/week (11; 6.7%). Cidofovir was administered for adenovirus, cytomegalovirus (CMV) and BK virus infection in 75 (45.5%), 64 (38.8%) and 51 (30.9%) patients, respectively. Among 158 patients with renal function data at baseline and EOT, 40 (25.3%) developed nephrotoxicity. In multivariable analyses, age (OR 1.04; P = 0.05), weight (OR 1.05; P = 0.01), CMV infection (OR 3.6; P = 0.02), liposomal amphotericin B (OR 8.06; P = 0.05) and IV voriconazole/posaconazole (OR 13.0; P = 0.003) were predictors of nephrotoxicity. Creatinine concentration was significantly higher at EOT (1.16 ±â€Š0.95 mg/dL) compared with baseline (0.91 ±â€Š0.39 mg/dL; P < 0.001), but improved by 2 weeks (0.91 ±â€Š0.84 mg/dL; P = 0.007) and 4 weeks (0.96 ±â€Š0.89 mg/dL; P = 0.03) post-EOT. Median viral load significantly declined for patients with adenovirus DNAaemia by EOT (P < 0.0001) and for patients with CMV DNAaemia by EOT + 4 weeks (P = 0.003), but not for patients with BK virus DNAaemia. CONCLUSIONS: One in four HCT recipients treated with IV cidofovir developed largely reversible nephrotoxicity. Careful selection of patients and close follow-up of renal function may minimize toxicity.

Epstein-Barr virus related post-transplant lymphoproliferative disorder prevention strategies in allogeneic hematopoietic stem cell transplantation.

Epstein-Barr virus associated post-transplant lymphoproliferative disorders (EBV PTLD) are recognized as a significant cause of morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplantation (alloHSCT). The number of patients at risk of developing EBV PTLD is increasing, partly as a result of highly immunosuppressive regimens, including the use of anti-thymocyte globulin (ATG). Importantly, there is heterogeneity in PTLD management strategies between alloHSCT centers worldwide. This review summarizes the different EBV PTLD prevention strategies being utilized including the alloHSCT and T-cell depletion regimes and the risk they confer; monitoring programs, including the timing and analytes used for EBV virus detection, as well as pre-emptive thresholds and therapy with rituximab. In the absence of an institution-specific policy, it is suggested that the optimal pre-emptive strategy in HSCT recipients with T-cell depleting treatments, acute graft vs host disease (GVHD) and a mismatched donor for PTLD prevention is (a) monitoring of EBV DNA post-transplant weekly using plasma or WB as analyte and (b) pre-emptively reducing immune suppression (if possible) at an EBV DNA threshold of >1000 copies/mL (plasma or WB), and treating with rituximab at a threshold of >1000 copies/mL (plasma) or >5000 copies/mL (WB). There is emerging evidence for prophylactic rituximab as a feasible and safe strategy for PTLD, particularly if pre-emptive monitoring is problematic. Future management strategies such as prophylactic EBV specific CTLs have shown promising results and as this procedure becomes less expensive and more accessible, it may become the strategy of choice for EBV PTLD prevention.

Very late-onset cytomegalovirus disease with ganciclovir resistance >15 years following renal transplantation.

Cytomegalovirus (CMV) infection is a significant cause of morbidity and mortality after solid organ transplantation. There has been a significant shift in disease epidemiology with the introduction of antiviral prophylaxis, with CMV disease occurring later and clinical presentations more atypical. We describe two cases of very late-onset CMV disease where first disease occurred 15 and 18 years post-renal transplantation, with both cases complicated by antiviral drug resistance. We subsequently review the published cases and literature of very late-onset CMV disease (onset > 10 years post-solid organ transplantation) as an increasingly recognized phenomenon which is emerging as an important aspect in improving long-term patient outcomes in the current era of renal transplantation.

Dynamics of Epstein-Barr virus on post-transplant lymphoproliferative disorders after antithymocyte globulin-conditioned allogeneic hematopoietic cell transplant.

BACKGROUND: The use of antithymocyte globulin (ATG) in allogeneic hematopoietic cell transplant (HCT) is associated with an increased risk of Epstein-Barr virus (EBV) reactivation and post-transplant lymphoproliferative disorders (PTLD). The dynamics and outcomes of EBV-DNAemia are not well described in this population. METHODS: We retrospectively assessed the kinetics of EBV-DNAemia after ATG conditioning of HCT recipients. Receiver operating characteristic (ROC) curves were used to assess EBV-DNAemia to predict EBV-PTLD in this group. RESULTS: A total of 174/405 (43%) consecutive HCT recipients from two centers met inclusion criteria of ATG conditioned, non-B-cell lymphoma patients. Of these with EBV-DNA measured using standardized IU/ml, 78.6% (92/117) developed EBV-DNAemia: 62% spontaneously resolved; 19% cleared after preemptive rituximab, and 13% developed EBV-PTLD. ROC curve analysis using maximum pre-EBV-PTLD EBV-DNAemia, demonstrated an AUC of 0.912 with EBV-DNAemia of 9782 IU/ml, associated with 82.6% sensitivity and 94.4% specificity for development of EBV-PTLD. Median time for EBV-DNAemia to increase from initial detection to >1000 IU/ml was 7 days; to >10 000 IU/ml, 12 days; and to >100 000 IU/ml, 18 days. Median EBV-DNAemia level prior to administration of rituximab was significantly lower in patients with successful preemptive treatment, compared with those who developed EBV-PTLD (3.41 log10  IU/ml [3.30-3.67] vs. 4.34 log10  IU/ml [3.85-5.13], p = .002; i.e., 2628 IU/ml vs. 21 965 IU/ml, respectively). CONCLUSIONS: EBV-DNAemia >10 000 IU/ml was the strongest predictor of the development of EBV-PTLD, and progression to this level was rapid in ATG-conditioned HCT recipients. This information may guide EBV-PTLD management strategies in these high-risk patients.

Consensus guidelines for the diagnosis and management of invasive aspergillosis, 2021.

Invasive aspergillosis (IA) in haematology/oncology patients presents as primary infection or breakthrough infection, which can become refractory to antifungal treatment and has a high associated mortality. Other emerging patient risk groups include patients in the intensive care setting with severe respiratory viral infections, including COVID-19. These guidelines present key diagnostic and treatment recommendations in light of advances in knowledge since the previous guidelines in 2014. Culture and histological-based methods remain central to the diagnosis of IA. There is increasing evidence for the utility of non-culture methods employing fungal biomarkers in pre-emptive screening for infection, as well as for IA diagnosis when used in combination. Although azole resistance appears to be uncommon in Australia, susceptibility testing of clinical Aspergillus fumigatus complex isolates is recommended. Voriconazole remains the preferred first-line antifungal agent for treating primary IA, including for extrapulmonary disease. Recommendations for paediatric treatment broadly follow those for adults. For breakthrough and refractory IA, a change in class of antifungal agent is strongly recommended, and agents under clinical trial may need to be considered. Newer immunological-based imaging modalities warrant further study, while surveillance for IA and antifungal resistance remain essential to informing the relevance of current treatment recommendations.

Managing haematology and oncology patients during the COVID-19 pandemic: interim consensus guidance.

INTRODUCTION: A pandemic coronavirus, SARS-CoV-2, causes COVID-19, a potentially life-threatening respiratory disease. Patients with cancer may have compromised immunity due to their malignancy and/or treatment, and may be at elevated risk of severe COVID-19. Community transmission of COVID-19 could overwhelm health care services, compromising delivery of cancer care. This interim consensus guidance provides advice for clinicians managing patients with cancer during the pandemic. MAIN RECOMMENDATIONS: During the COVID-19 pandemic: In patients with cancer with fever and/or respiratory symptoms, consider causes in addition to COVID-19, including other infections and therapy-related pneumonitis. For suspected or confirmed COVID-19, discuss temporary cessation of cancer therapy with a relevant specialist. Provide information on COVID-19 for patients and carers. Adopt measures within cancer centres to reduce risk of nosocomial SARS-CoV-2 acquisition; support population-wide social distancing; reduce demand on acute services; ensure adequate staffing; and provide culturally safe care. Measures should be equitable, transparent and proportionate to the COVID-19 threat. Consider the risks and benefits of modifying cancer therapies due to COVID-19. Communicate treatment modifications, and review once health service capacity allows. Consider potential impacts of COVID-19 on the blood supply and availability of stem cell donors. Discuss and document goals of care, and involve palliative care services in contingency planning. CHANGES IN MANAGEMENT AS A RESULT OF THIS STATEMENT: This interim consensus guidance provides a framework for clinicians managing patients with cancer during the COVID-19 pandemic. In view of the rapidly changing situation, clinicians must also monitor national, state, local and institutional policies, which will take precedence. ENDORSED BY: Australasian Leukaemia and Lymphoma Group; Australasian Lung Cancer Trials Group; Australian and New Zealand Children's Haematology/Oncology Group; Australia and New Zealand Society of Palliative Medicine; Australasian Society for Infectious Diseases; Bone Marrow Transplantation Society of Australia and New Zealand; Cancer Council Australia; Cancer Nurses Society of Australia; Cancer Society of New Zealand; Clinical Oncology Society of Australia; Haematology Society of Australia and New Zealand; National Centre for Infections in Cancer; New Zealand Cancer Control Agency; New Zealand Society for Oncology; and Palliative Care Australia.

New advances in the management of cytomegalovirus in allogeneic haemopoietic stem cell transplantation.

Cytomegalovirus (CMV) viraemia continues to be a frequent complication in the post-haemopoietic stem cell transplantation period despite a low incidence of CMV end-organ disease. Several significant advances in the understanding and management of CMV infection have occurred in the last few years including improved diagnostics, monitoring of CMV immunity, availability of novel anti-CMV drugs, and emerging use of immunotherapies including CMV-specific T-cell infusions. In addition to reviewing these advances we also explore some of the more practical prescribing issues of the older and newer CMV drugs including cost, toxicity and drug interactions to help clinicians navigate this new era of CMV management.

Fatal disseminated visceral varicella zoster virus infection in a renal transplant recipient.

We report a case of fatal disseminated varicella zoster virus (VZV) with delayed-onset rash in a 66-year-old female more than 2 years following uncomplicated deceased donor renal transplantation. Whilst on a stable regimen of maintenance immunosuppression, the patient presented with chest and abdominal pain with concomitant hepatitis and pancreatitis. After pursuing multiple other potential causes of her symptoms, the correct diagnosis of VZV was only suspected after the development of a widespread vesicular rash-11 days after her initial symptoms. Despite antiviral therapy and inotropic support in the intensive care unit, the patient died. Simultaneous VZV hepatitis and pancreatitis in solid organ transplant recipients is uncommon. The new inactivated VZV vaccines have the potential to prevent post-transplant infections, with promising early clinical data on safety and efficacy in renal transplant recipients. VZV is an important preventable infection that should be considered in immunocompromised patients, even in the absence of rash.

Invasive fungal disease and cytomegalovirus infection: is there an association?

PURPOSE OF REVIEW: Invasive fungal disease (IFD) and cytomegalovirus (CMV) infections occur frequently, either concomitantly or sequentially in immune-compromised hosts. Although there is extensive knowledge of the risk factors for these infections as single entities, the inter-relationship between opportunistic fungii and CMV has not been comprehensively explored. RECENT FINDINGS: Both solid organ and stem cell transplant recipients who develop CMV invasive organ disease are at an increased risk of developing IFD, particularly aspergillosis and Pneumocystis pneumonia (PCP). Moreover, CMV viremia and recipient CMV serostatus also increased the risk of both early and late-onset IFD. Treatment-related factors, such as ganciclovir-induced neutropenia and host genetic Toll-like receptor (TLR) polymorphisms are likely to be contributory. Less is known about the relationship between CMV and IFD outside transplantation, such as in patients with hematological cancers or other chronic immunosuppressive conditions. Finally, few studies report on the relationship between CMV-specific treatments or the viral/antigen kinetics and its influence on IFD management. SUMMARY: CMV infection is associated with increased risk of IFD in posttransplant recipients because of a number of overlapping and virus-specific risk factors. Better understanding of how CMV virus, its related treatment, CMV-induced immunosuppression and host genetic factors impact on IFD is warranted.